Comparative capacity of four antifungal agents to stimulate murine macrophages to produce tumour necrosis factor alpha: an effect that is attenuated by pentoxifylline, liposomal vesicles, and dexamethasone

Abstract

The efficacy and toxicity of certain antifungal agents may be related to their ability to induce the production of cytokines by mononuclear phagocytes. The capacity of incremental concentrations of fluconazole, 5-fluorocytosine (5-FC), amphotericin B (AmB), and liposomal AmB (LAB) to stimulate murine peritoneal and RAW 264.7 macrophages to secrete tumour necrosis factor alpha (TNFα) after 3, 6 and 24 h incubation was assessed by L929 cytotoxic bioassay. Fluconazole (2.5-40 mg/L) and 5-FC (25-100 mg/L) did not have a stimulatory effect. However, AmB (0.25-10 mg/L) clicited TNFα production by macrophages. This response was concentration-dependent, and peak TNFα levels were detected between 3 and 6 h. This effect was attenuated by incorporation of AmB into liposomal vesicles and by pretreating macrophages with pentoxifylline or dexamethasone. AmB 1 mg/L in combination with 1 × 10⁶ cfu of Candida albicans stimulated peritoneal macrophages to produce similar quantities of TNFα as AmB alone, and two- to four-fold more TNFα than C. albicans alone. Thus, this study suggests that: (1) the immuno-modulatory activity and toxicities of AmB, in part, may be attributed to the capacity of this drug to stimulate macrophages to secrete TNFα, (2) the TNFα that is produced by macrophages in response to AmB may have clinical relevance even in the face of C. albicans infection, and (3) the failure of fluconazole, 5-FC, and LAB to elicit a TNFα response may explain their improved side-effect profiles.